Cytoskeletal structure in cells harboring two mutations: R133C in NOTCH3 and 5650G&gt;A in mitochondrial DNA

Annunen-Rasila, Johanna; Kärppä, Mikko; Finnilä, Saara; Ylä‐Outinen, Heli; Veijola, Johanna; Tuominen, Hannu; Majamaa, Kari

doi:10.1016/j.mito.2006.11.004

Cited by 5 publications

(5 citation statements)

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“…He presented with typical features of CADASIL but muscle biopsy revealed ragged red fibers and abnormal mitochondria on ultrastructural investigations [5]. Further morphological studies revealed that the tubulin network was sparse and formed asters, whereas the vimentin and actin networks were intact [22]. Mitochondria were reduced in number as well as the inner mitochondrial network [22].…”

Section: Resultsmentioning

confidence: 99%

“…Further morphological studies revealed that the tubulin network was sparse and formed asters, whereas the vimentin and actin networks were intact [22]. Mitochondria were reduced in number as well as the inner mitochondrial network [22]. In addition to the ragged red fibers, COX-negative fibers were described [22].…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondria were reduced in number as well as the inner mitochondrial network [22]. In addition to the ragged red fibers, COX-negative fibers were described [22]. The mtDNA mutation was heteroplasmic with a heteroplasmy rate of 99% in skeletal muscle, 96% in the buccal epithelium, 95% in the skin, and 65% in the blood [5].…”

Section: Resultsmentioning

confidence: 99%

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Neuromuscular Implications in CADASIL

Finsterer¹

2007

Cerebrovasc Dis

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Objectives: Recent studies indicate that Notch3 gene mutations not only manifest as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) but also in the peripheral nerves and skeletal muscles. Methods: A MEDLINE search with appropriate terms was carried out. Six articles, dealing with neuromuscular involvement in CADASIL, were selected and reviewed. Results: Several case studies presented CADASIL patients with clinical features of myopathy. Neurological diagnostic workup in these patients revealed weakness, wasting, reduced/exaggerated tendon reflexes, abnormal nerve conduction and electromyography, muscle biopsy with ragged red muscle fibers, reduced COX staining, decreased complex I respiratory chain activity, abnormally structured mitochondria, or mitochondrial DNA (mtDNA) mutations, such as G5650A in the tRNAAla gene, or various other mtDNA substitutions. Additionally, fibroblasts in skin biopsy may show reduced complex V respiratory chain activity. Conclusions: These findings suggest Notch3 mutations to be associated with mitochondrial disease, particularly affecting the skeletal muscle. Whether mtDNA mutations were induced by Notch3 mutations, by oxidative stress due to chronic hypoxia, resulting from arteriopathy, or occurred spontaneously remains elusive. Patients carrying Notch3 mutations should be systematically investigated for neuromuscular involvement, which may have therapeutic and prognostic implications for these patients.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Neuromuscular Implications in CADASIL

Finsterer¹

2007

Cerebrovasc Dis

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“…The first in vitro studies were based on primary cell models, which included VSMCs [ 68 , 69 ], skin fibroblasts [ 70 ], and myoblasts [ 71 ] derived from CADASIL patients; HS683 oligodendrocytes transfected with mutant NOTCH3 [ 72 ]; human embryonic kidney 293 cells (HEK293) and neuroblastoma cells (SH-SY5Y) in which the expression of mutant NOTCH3 was inducible using the tetracycline (Tet)-on regulatory system [ 15 , 73 – 77 ]; primary mouse embryonic fibroblasts (MEFs) from mice carrying mutant NOTCH3 transgenes [ 78 ]; and Lec1-Chinese hamster ovary (CHO Lec1) cell lines transfected with plasmids encoding murine Notch3 fragments bearing CADASIL-like mutants [ 78 ].…”

Section: Disease Modelsmentioning

confidence: 99%

CADASIL from Bench to Bedside: Disease Models and Novel Therapeutic Approaches

Manini

Pantoni

2021

Mol Neurobiol

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by NOTCH3 mutations and characterized by typical clinical, neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.

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“…172 Some of the CADASIL patients also shared an R133C mutation in Noch3 gene, although in nine patients C5650T was the only mutation. 173 Exercise intolerance and myoglobinuria. The syndrome of exercise intolerance, cramps, and myoglobinuria (presence of myoglobin in the urine, usually associated with rhabdomyolysis) is a common manifestation of metabolic myopathies and has been associated with several specific inborn errors of glycogen or lipid metabolism.…”

Section: The Clinical Phenotypes Of Mitochondrial Trna Mutationsmentioning

confidence: 99%